Albumin in a flexible polymeric container

ABSTRACT

A flexible polymeric container for holding albumin. The container is made of a sheet of flexible polymeric film formed into a bag having a cavity enclosed by a first wall, an opposing second wall, and seals about a periphery of the first and second walls. The seals join an interior portion of the opposing first and second walls and create a fluid-tight chamber within the cavity of the container for storing a concentration of the albumin. A method of packaging the albumin protein into a flexible polymeric container is also provided. Therein a flexible polymeric material is converted into bags, the bags are filled with a quantity of albumin by a filler, and a seal area of the bags is sealed to enclose the albumin within the bag.

DESCRIPTION

[0001] 1. Technical Field

[0002] The present invention relates generally to the packaging of aprotein in a flexible polymeric container, and more specifically to themass-packaging of albumin in flexible polymeric containers in an asepticenvironment of a form-fill-seal packaging machine.

[0003] 2. Background of the Invention

[0004] Many peptides and proteins for pharmaceutical or other use areknown, including glycoproteins, lipoproteins, imunoglobulins, monoclonalantibodies, enzymes, blood proteins, receptor proteins, and hormones.

[0005] One type of such compound is albumin. Albumin is asulfur-containing, water-soluble protein that congeals when heated, andoccurs in egg white, milk, blood, and other animal and vegetable tissuesand secretions. Albumin is often utilized as a blood expander to assistin maintaining a patient's blood pressure, or sometimes to assist withincreasing a patient's blood pressure during blood loss.

[0006] Proteins, such as albumin, are adsorbed by most man-madematerials, including liquid containers made of various polymers.Adsorption of the protein onto the artificial polymeric surface resultsin a lowering of the protein content of that solution. Some proteinsolutions can be adversely affected by protein adsorption ontoartificial surfaces through a process called denaturing. Denaturing is aprocess whereby the protein is not permanently adsorbed onto thepolymeric container, but rather the protein molecules are adsorbed ontothe container and then released. The adsorption and release can changethe shape of the molecule (i.e., denature it). Often, when proteinmolecules in protein drug solutions have undergone denaturing, there maylose their efficacy and utility. Accordingly, to date proteins such asalbumin have been stored for individual use in glass vials in order toavoid the risk of denaturing. Because of the cost encountered inproducing, packaging, boxing, shipping and storing glass vials, as wellas the cost and weight of the glass vial, and the ease with which theglass vial may break, a more efficient, inexpensive and user friendlymeans of packaging proteins such as albumin to possibly eliminate theabove drawbacks is desirable.

[0007] One type of packaging utilized for packaging non-proteinpharmaceuticals is polymeric bags formed with a form-fill-seal packagingmachine. Form-fill-seal packaging machines are typically utilized topackage a product in a flexible container. The form-fill-seal packagingmachine provides an apparatus for packaging certain pharmaceuticals andmany other products in an inexpensive and efficient manner.

[0008] Pursuant to FDA requirements, certain pharmaceuticals packaged inform-fill-seal packages are traditionally sterilized in a post-packagingautoclaving step. The post-packaging step includes placing the sealedpackage containing the pharmaceutical in an autoclave and steamsterilizing or heating the package and its contents to a requiredtemperature, which is often approximately 250° F., for a prescribedperiod of time. This sterilization step operates to kill bacteria andother contaminants found inside the package, whether on the inner layerof film or within the pharmaceutical itself.

[0009] Certain packaged pharmaceuticals, including certain proteins suchas albumin, however, generally cannot be sterilized in such a manner.This is because the heat required to kill the bacteria in theautoclaving process destroys or renders useless certain pharmaceuticals.Further, in the case of albumin protein, the heat may operate to congealthe protein.

[0010] Form-fill-seal packaging may also present other problems beyondsterilization concerns when packaging certain proteins such as albumin.Specifically, conventional form-fill-seal packaging machinery introducesheat to certain areas of the polymeric material of the package to createseals. If the heat contacts the protein during the sealing process, theprotein may congeal or otherwise denature such as duringhigh-temperature sterilization. Further, since certain proteins such asalbumin operate as insulators, all seal areas must be free of theprotein in order for the polymeric materials to be heat sealed together.If any protein such as albumin is present in the seal area prior tosealing, the integrity of the seal may be jeopardized.

[0011] Thus, a convenient and cost-effective means for packaging certainproteins, including proteins such as albumin is desirable.

SUMMARY OF THE INVENTION

[0012] The present invention provides a flexible polymeric container forholding a concentration of peptides and/or proteins. Such peptides andproteins include: glycoproteins, lipoproteins, imunoglobulins,monoclonal antibodies, enzymes, blood proteins, receptor proteins, andhormones. Additionally, the present invention provides a method ofpackaging such a compound in a flexible polymeric container. Generally,the flexible polymeric container comprises a sheet of flexible polymericfilm formed into a bag. The bag has a cavity enclosed by a first walland an opposing second wall. The bag further has seals about a peripheryof the first and second walls that join an interior portion of theopposing first and second walls to create a fluid-tight chamber withinthe cavity of the container. A concentration of the compound is storedwithin the fluid-tight chamber. In one embodiment, the compound isalbumin.

[0013] According to one aspect of the present invention, the flexiblepolymeric container for holding a concentrate of water-soluble albumincomprises a sheet of flexible polymeric material that is initiallyconverted into a tube with a former, and is subsequently converted intoa series of adjacent bags. The bags have a first side member, a secondside member peripherally sealed to the first side member, and a cavitybetween an interior of the first and second side members. A quantity ofa concentration of water-soluble albumin is located within the cavity ofthe bag. The openings of the bags are subsequently sealed to create afluid-tight chamber.

[0014] According to another aspect of the present invention, thecontainer has a plurality of peripheral edges. Three of the peripheraledges are sealed with heat, and one of the peripheral edges contains afold that separates the first wall or first side member from theopposing second wall or second side member.

[0015] According to another aspect of the present invention, a fitmentis connected to the container adjacent the fold. The fitment extendsfrom the outer shell of the container at the fold and has a sealedpassageway that cooperates with the fluid-tight chamber of thecontainer. The sealed passageway extends into the cavity of thecontainer to allow the albumin to be released from the fluid-tightchamber. A chevron may be located a distance from the opposing sides ofthe fitment, and along the fold, to assist drainage of the albumin fromthe container.

[0016] According to another aspect of the present invention, theperipheral edge of the container opposing the fold contains a first sealand a second seal. The first and second seals join the first and secondopposing walls. An aperture is located between the first seal and thesecond seal, and extends through the first and second opposing walls.

[0017] According to another aspect of the present invention, theflexible polymeric sheet material comprises a laminate film having anoutside layer of linear low density polyethylene, a gas barrier layer, acore layer of polyamide, and an inside layer of linear low densitypolyethylene. The layers are bonded together by a polyurethane adhesive.

[0018] According to another aspect of the present invention, albumin inconcentrations of 20% and 25% is packaged in the flexible polymericcontainer. Additionally, the flexible polymeric containers may have avolume of 50 ml. or 100 ml.

[0019] According to another aspect of the present invention, a method ofpackaging albumin protein comprises providing a flexible polymericcontainer having an opening extending from a cavity of the polymericcontainer, providing a quantity of a concentration of albumin in asterile solution, inserting the albumin under a pressure into the cavityof the polymeric container through the opening, and sealing the openingto secure the liquid albumin within a fluid-tight chamber of the cavityof the polymeric container.

[0020] According to another aspect of the present invention, a filler isused to insert the albumin into the flexible container. The filler has adistal tip with adjacent first and second interior passageways. Thefirst interior passageway has a larger cross-sectional area than thesecond interior passageway. The second interior passageway extendsadjacent the first interior passageway to an exterior of the tip, andthe albumin is dispersed from the filler through the second interiorpassageway.

[0021] According to another aspect of the present invention, theinterface between the first and second interior passageways is interiorof an exterior of the tip, and the second interior passageway extends tothe exterior of the tip. The albumin is maintained at the interfacebetween the first and second interior passageways during a suspension offilling of the bags.

[0022] According to another aspect of the present invention, a sheath islocated exterior to a portion of the filler adjacent the tip. The sheathprevents contact between the polymeric container and the filler.

[0023] According to another aspect of the present invention, the sheathis concentric with the filler. An air passageway extends between aninterior of the sheath and an exterior of the filler. Further,sterilized air passes through the air passageway and is expelledadjacent the tip of the filler and upstream of the albumin exit.

[0024] According to another aspect of the present invention, albumin ispackaged in a series of flexible polymeric containers with aform-fill-seal packaging machine. A quantity of filtered albumin and aflexible polymeric material is provided, and the form-fill-sealpackaging machine converts the flexible polymeric material into a seriesof bags. The bags are filled with a quantity of albumin within theform-fill-seal packaging machine, and a seal area of the bags is sealedwith the packaging machine to enclose the quantity of the albumin in thebags.

[0025] According to another aspect of the present invention, theadjacent bags in the series of bags are initially connected, aresequentially filled with a quantity of albumin, and are separatedfollowing the filling of each bag.

[0026] According to another aspect of the present invention, theform-fill-seal packaging machine has an aseptic area. The sterilizedflexible polymeric material is provided within the aseptic area, and isformed into bags within the aseptic area. Additionally, the filteredalbumin is inserted into the bags in the aseptic area, and the bags aresealed within the aseptic area to form a fluid-tight container.

[0027] According to another aspect of the present invention, albumin ispackaged in a series of flexible polymeric containers in aform-fill-seal packaging machine with the following process: convertingflexible polymeric material into a tube with a former in theform-fill-seal packaging machine; converting the tube into a series ofbags in the form-fill-seal packaging machine; sequentially filling thebags with a quantity of albumin within the form-fill-seal packagingmachine; and, sealing a seal area of the bags with the packaging machineto enclose the quantity of the albumin within the bags. The bags may befilled with a filler that discharges albumin from the filler and intothe bag without contacting the seal area of the opening of the bag.

[0028] According to yet another aspect of the present invention, albuminis packaged in a flexible polymeric container with the followingprocess: providing a concentrate of albumin; providing a packagingmachine having a forming assembly, a filling assembly, and a sealingassembly, each of which is located within an interior asepticenvironment of the packaging machine; providing a flexible polymericfilm; forming the flexible polymeric film into an elongated tube withthe forming assembly; sealing a portion of the elongated tube ofpolymeric film with the sealing assembly, the sealed polymeric filmbeing dimensioned in the shape of a bag having seal areas about aperiphery thereof, a cavity located within the bag and between the sealareas, and an opening extending from the cavity to an exterior of thebag; filling the bag with albumin under pressure through the fillingassembly, the filling assembly having a fill tube extending through theopening of the bag and into the cavity of the bag, and a sheathconcentric to an exterior of the fill tube, the fill tube directing thealbumin into an interior of the bag a distance away from a periphery ofthe opening of the bag, and the sheath limiting contact between the filltube and the bag; and, sealing the opening of the bag to retain thealbumin within the cavity of the bag.

[0029] Accordingly, a flexible polymeric container for storing albuminmade in accordance with the present invention provides an inexpensive,easily manufactured, and efficient package and process which eliminatesthe drawbacks associated with prior packages and processes for packagingalbumin.

[0030] Other features and advantages of the invention will be apparentfrom the following specification taken in conjunction with the followingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] To understand the present invention, it will now be described byway of example, with reference to the accompanying drawings in which:

[0032]FIG. 1 is a cross-sectional elevation view of a form-fill-sealpackaging machine for manufacturing a flexible polymeric containerholding a concentration of albumin of the present invention;

[0033]FIG. 2 is a schematic view of the process for manufacturing theflexible polymeric container holding a concentration of albumin of thepresent invention;

[0034]FIG. 3 is a front elevation view of the flexible polymericcontainer holding a concentration of albumin of the present invention;

[0035]FIG. 4 is a partial side elevation view of the flexible polymericcontainer holding a concentration of albumin of FIG. 3;

[0036]FIG. 5 is a side elevation view of a partial filler assembly ofthe present invention;

[0037]FIG. 6 is an enlarged side elevation view of a portion of thefiller assembly of FIG. 5;

[0038]FIG. 7 is a cross-sectional side elevation view of a sheath forthe filler assembly of the present invention;

[0039]FIG. 8 is an end elevation view of the sheath of FIG. 7;

[0040]FIG. 9 is a schematic cross-sectional view of an embodiment of thefilm laminate structure of the present invention; and,

[0041]FIG. 10 is a cross-sectional view of the end of the fill tube andsheath of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0042] While this invention is susceptible of embodiments in manydifferent forms, there is shown in the drawings and will herein bedescribed in detail preferred embodiments of the invention with theunderstanding that the present disclosure is to be considered as anexemplification of the principles of the invention and is not intendedto limit the broad aspect of the invention to the embodimentsillustrated.

[0043] As identified above, the breadth of the present disclosureincludes the packaging of any type of certain pharmaceutical compoundssuch as peptides and proteins for pharmaceutical or other use. Suchcompounds are known and include: glycoproteins, lipoproteins,imunoglobulins, monoclonal antibodies, enzymes, blood proteins, receptorproteins, and hormones. For purposes of example, however, the detaileddescription of the present invention focuses on the packaging of albuminin a flexible polymeric container.

[0044] Referring now in detail to the FIG. 3, there is shown a flexiblepolymeric container 12 holding a concentration of albumin of the presentinvention. The flexible polymeric container 12 is preferablymanufactured by an aseptic form-fill-seal packaging machine 10 as shownin FIG. 1, and utilizing the process schematically illustrated in FIG.2.

[0045] The aseptic form-fill-seal packaging machine 10 generallyincludes an unwind section 14, a film sterilizing section 16, a filmdrying section 18, an idler roller/dancer roller section 20, a nippeddrive roller assembly section (not shown), a forming assembly section22, a fin seal assembly section 24, a fitment attaching assembly section26, a filling assembly section 30, an end sealing/cutting assemblysection 32, and a delivery section (not shown). Each of these assembliesdownstream of the unwind section 14 is contained within the internalaseptic environment of the aseptic form-fill-seal packaging machine 10.

[0046] One of the functions of each of the various assemblies of theform-fill-seal packaging machine 10 is as such: the unwind section 14contains a roll of the flexible polymeric film 34 that is ultimatelyformed into the container; the film sterilizing section 16 provides aperoxide bath to sterilize the film 34; the film drying section 18provides a means for drying and cleaning the peroxide from the film 34;the forming assembly 22 provides a forming mandrel 36 to convert the webof film into a tube 38 that ultimately becomes the flexible container orbag 12; the fin seal assembly 24 provides the longitudinal seal 40 onthe tube 38 that ultimately becomes the longitudinal seal 40 on theflexible container 12, thereby longitudinally sealing the formed tube38; the fitment attachment assembly 26 attaches a fitment 42 to the tube38; the filling assembly 30 includes a filler 44 that fills the flexiblecontainers 12 with a substance, that being a concentration ofwater-soluble albumin in the present preferred application; and, the endsealing/cutting assembly 32 contains cutting and sealing jaws 46 thatform the end seals 76,78 of the flexible polymeric containers 12 toenclose the albumin within the flexible polymeric container 12.

[0047] In the preferred embodiment, the albumin utilized to be packagedin the flexible polymeric container 12 is either a 20% human albumin ora 25% human albumin. To achieve the required concentration level, thealbumin is typically combined with sterile water and stabilizers.Further, prior to packaging the albumin concentration is pasteurized andstored in large stainless steel holding tanks (not shown) having avolumetric capacity of approximately 500-600 liters, at approximately 2°C. to 8° C. Immediately before packaging, the albumin tanks are removedfrom refrigeration and allowed to equilibrate to the packaging roomtemperature (approximately 68° F.). It is important to process albuminat temperatures which do not result in denaturing of the protein,approximately below 60° C. However, anywhere between 0° C. and 60° C.,and more preferably between 20° C. and 45° C. is appropriate.Additionally, in one embodiment the process temperatures 68° F. to 77°F. Additionally, the albumin is filtered through a 0.2 micron filter asit enters the packaging machine 10.

[0048] The flexible polymeric film 34 utilized in the preferredembodiment of the present invention is a linear low density polyethylenelaminate. It has been found that such a film with a gas barrier isparticularly suitable for housing oxygen labile solutions, such as theidentified proteins, including albumin. Specifically, it has been foundthat this film reduces or eliminates the denaturing process previouslyassociated with placing proteins, such as albumin, in a plasticcontainer. As shown in FIG. 9, in the preferred embodiment the laminatefilm 34 has an outside layer of linear low density polyethylene (LLDPE)52, a gas barrier layer 54, a core layer of polyamide 56, and an insidelayer of linear low density polyethylene 58, the layers being bondedtogether by a polyurethane adhesive 60. Most preferably, the materialrequirements of the laminate structure has the followingcharacteristics: a LLDPE layer (approximately 61±10 μm) 52, apolyurethane adhesive layer 60, a polyvinylidene chloride (PVDC) layer(approximately 19±5 μm) 54, a polyurethane adhesive layer 60, a nylonlayer (approximately 15±5 μm) 56, a polyurethane adhesive layer 60, andLLDPE layer (approximately 61±10 μm) 52. In total, the thickness of thefilm is approximately 160±25 μm. Additionally, the PVDC layer 54 is mostpreferably manufactured by Dow Chemical and sold under the trademarkSARAN. Such a film is disclosed in U.S. Pat. No. 4,629,361. U.S. Pat.No. 4,629,361 is assigned to the assignee of the present invention, andis incorporated herein, and made a part hereof, by this reference. Thisfilm 34 is manufactured by Fujimori under the trade name FTR-13F.

[0049] Prior to usage, the internal aseptic area of the packagingmachine must be sterilized each day. This is accomplished with ahydrogen peroxide fog which is passed through the aseptic area of thepackaging machine.

[0050] As seen in FIG. 1, the roll of film 34 is located in the unwindsection 14 of the packaging machine 10. During use, the film 34 istransferred through a hydrogen peroxide bath 16 to sterilize the filmbefore entering the aseptic area of the packaging machine 10. Thissterilization step cleans the web of film so that it can be utilized tocreate a sterile product. Sterilization and cleansing of the film iscritical in the medical industry when one is packaging parenternal orenteral products. This sterilization step is especially critical whenthe resultant product is not to be terminally sterilized, i.e., when thepackaging machine is an aseptic packaging machine. After the film hasbeen washed, cleaned or sterilized, liquid and other residue, forexample the chemical sterilant or wetting agent such as the hydrogenperoxide typically remains on the film. Thus, it is necessary to removethe liquid and/or residue from the film 34. An air knife (a stream ofair blown across the web of film so that the liquid contained thereon isblown off the film) located in the film drying section 18 is utilized toremove liquid and other residue from the film 34 as the film enters theaseptic area of the packaging machine.

[0051] In the aseptic area of the packaging machine 10, the film 34passes through the dancer roller section 20 and the drive roller sectionprior to entering the forming assembly section 22. Before entering theforming assembly 22 the web of film 34 is substantially planar, and hasa first surface 62 and a second surface 64. The first surface 62 facesdownward as the film enters the forming assembly 22 and ultimatelybecomes an interior of the container 12, while the second surface 64faces upward as the film enters the forming assembly 22 and ultimatelybecomes the outside of the container 12.

[0052] As shown in FIGS. 3 and 4, the film 34 additionally has atheoretical fold-line approximately located about a centerline of thelength of the web of film 34. The theoretical fold-line becomes a foldarea 67 that separates the first side member 66 or first wall from thesecond side member 68 or second wall of the container 12.

[0053] A forming mandrel 36 is located in the forming assembly section22. The forming mandrel 36 assists in converting the substantiallyplanar web of polymeric material 34 into an elongated and substantiallytubular member 38. It is understood that the elongated tubular member38, or tube, is generally not cylindrical, but rather has an oblongshape as shown in FIG. 4. In connection with the identification of theareas of the web of film as described above, after the film 34 traversesthrough the forming assembly 22, the first surface 62 of the first sidemember 66 opposes the first surface 62 of the second side member 68.

[0054] Once the tubular member 38 is formed, the tubular member receivesa longitudinal seal 40 in the fin seal assembly section 24, and afitment 42 is connected to the tube 38 in the fitment attachmentassembly 26. Specifically, fitment 42 is attached to and extends fromthe outer shell of the container 12 at the fold area 67 with the use ofa heated assembly to seal the fitment 42 to the fold area 67 of thecontainer 12. Typically, the fitment sealer operates at a temperaturefrom about 415° F. to about 450° F., and with a pressure from about 55psig to about 70 psig, although any range within these identified rangesis acceptable. As shown in FIG. 4, the fitment 42 has a sealedpassageway that cooperates with the interior of the tube 38.Specifically, the passageway extends into and creates a fluidcommunication with the cavity 82 of the container to allow the albuminto be released from the fluid-tight chamber. It should be understoodthat in some embodiments the albumin may be injected into the cavity 82of the container 12 through the fitment 42.

[0055] The fin seal assembly 24 introduces heat and pressure to the film34 to create the longitudinal seal 40 at the peripheral edge of the tube38 that opposes the fold area 67. Typically, the fin seal assemblyoperates at a temperature from about 350° F. to about 380° F., and witha pressure from about 40 psig to about 80 psig, although any rangewithin these identified ranges is acceptable In the preferred embodimentof the container 12 as shown in FIG. 3, the longitudinal seal 40comprises a first longitudinal seal 70 and a second longitudinal seal72. The first and second longitudinal seals 70,72 join the first surface62 of the first wall 66 to the opposing first surface 62 of the secondwall 68. An aperture 74, typically utilized to hang a formed container12, is created between the first longitudinal seal 70 and the secondlongitudinal seal 72. Accordingly, the aperture 74 extends through thefirst and second opposing walls 66,68.

[0056] The sealed tubular member 38 traverses from the fin seal assembly24 to the filling assembly 30 and the end sealing assembly 32. At theend sealing assembly 32, the form-fill-seal packaging machine 10utilizes heat and pressure to convert the sealed tube 38 into a seriesof bags 12, also referred to as containers 12. Typically, the endsealing assembly operates at a temperature from about 375° F. to about405° F., and with a pressure from about 500 psig to about 850 psig,although any range within these identified ranges is acceptable. Thesealed tube 38 first receives a bottom seal 76 to initially form the bag12 having a cavity 82 located between the first and second sides 66,68of the container 12 and the bottom seal 76 of the container, and anopening 80 that extends from the cavity 82 of the container 12 to anexterior of the container 12. It should be understood that during theform-fill-seal manufacturing process, the opening 80 extends from thecavity 82 of the container 12 into the center of the tube 38. Once thebottom seal 76 is created, the bag 12 is filled with the albumin throughthe opening 80, and then the top seal 78 is formed, thus sealing orclosing the opening 80 and creating a fluid-tight chamber 82 wherein thealbumin is retained. Further, once the bottom seal 76 is created, thepolymeric film 34 can be said to be dimensioned in the shape of the openbag 12, having seal areas about its periphery (the longitudinal seal 34opposing the fold area 67, and the bottom seal 76 joining the fold area67 and the longitudinal seal 40), and having a cavity 82 located withinthe bag 12 and between the seal areas 40, 76 and the fold area 67. Thus,with a form-fill-seal packaging process, the finished container 12 hassealed areas on three sides of the bag 12: the top seal 78, the bottomseal 76, and the longitudinal seal 40. The longitudinal seal 40 joinsthe top seal 78 and the bottom seal 76. In the preferred process, thetop seal 78 of a first bag 12 is formed at the same time as the bottomseal 76 of an adjacent upstream bag 12 with the end sealing assembly 32.As such, adjacent bags 12 in the series of bags 12 are initiallyconnected, both by being part of the tubular member 38 that forms thebags 12, as well as by having end seals that are formed with the sameend sealing assembly 32.

[0057] In the preferred embodiment of the process for creating andfilling containers of present invention with albumin as illustrated inFIGS. 1 and 2, the containers 12 are filled with the albumin through afilling assembly 30 that extends down the tube 38. The filling assembly30 thus fills the cavity 82 of the bag 12 through the opening 80 of thein-process three-sided and open bag 12.

[0058] The filling assembly 30 of the preferred embodiment isillustrated in FIGS. 5-8 and 10. As such, the filling assembly 30comprises a pressurized filler 44 made up of a fill tube 84, and asheath 86 located concentrically about the perimeter of the fill tube84. The filler 44 typically operates under a solution line pressure offrom about 4 psig. to about 20 psig, however, any range of pressureswithin the identified range is acceptable. In the preferred embodiment,the filler operates under a solution line pressure of from about 10psig. to about 16 psig, and most preferably under a solution linepressure of from about 12 psig. to about 16 psig. The identified rangesare utilized in an attempt to reduce turbulence and splashing of thealbumin or other protein as it is inserted into the container 12. Asexplained above, after the bottom seal 76 is created, the bag 12 isfilled with the albumin through the filling assembly 30, the top seal 78is created simultaneously with the bottom seal 76 of the next bag, thenext bag 12 of the tube 38 is sequentially filled, and so on and soforth. Thus, adjacent bags 12 in the series of bags 12 are initiallyconnected, and are then separated following sequentially filling andsealing of each respective bag 12.

[0059] As shown in FIG. 5, in the preferred embodiment, the filler 44 ofthe filling assembly 30 is configured as a tube 86 over a tube 84. Thesheath tube 86 is situated concentric about the fill tube 84, with anair passageway 88 extending in the space between the inner diameter ofthe sheath tube 86 and the outer diameter of the fill tube 84.Sterilized air passes through the air passageway and is expelledadjacent a tip of the fill tube 84, upstream of a fill tube exit 92.

[0060] In a preferred embodiment of the fill tube 84 as shown in FIG. 5,the fill tube 84 has a venturi 85 in that it tapers from a firstdiameter to a second larger diameter about its length. Further, as shownin FIG. 6, the tip 90 of the fill tube 84 has a first interiorpassageway 94 concentric with and adjacent a second interior passageway96. And, in a preferred embodiment of the present invention, the firstinterior passageway 94 is generally circular in cross-sectional shape,having a first interior diameter, and the second interior passageway 96is generally circular in cross-sectional shape, having a second interiordiameter. The interior diameter, and thus the cross-sectional area ofthe first interior passageway 94 is dimensioned larger than the interiordiameter, and thus the cross-sectional area of the second interiorpassageway 96. An interface 98 connects the first interior passageway 94and the second interior passageway 96 at a location that is interior ofan exterior of exit 92 of the tip 90 of the filler 44. In a preferredembodiment, the interface comprises a chamfered step 98 between thefirst and second interior passageways 94,96 to sharply reduce thediameter from the first interior passageway 94 to the second interiorpassageway 96. The interface 98 between the first and second passageways94,96 provides a important function in the operation of the filler.Since the albumin is dispensed from the exit of the second interiorpassageway 96 of the filler 44, capillary forces in the fill tubeoperates to have the meniscus of the albumin reside at the interface 98between the first and second passageways 94,96 during a stoppage infilling instead of at the exit 92 of the second passageway. Thus, eventhough the albumin is dispersed from the filler 44 through the secondinterior passageway 96, during each suspension in filling in betweensequential filling of the bags 12, the albumin is maintained interior toand a distance from the exit of the filler 44, and at the interface 98of the first and second passageways 94,96. Such a configuration greatlyassists in preventing migration of the albumin from the exit of thefiller. Any migration may allow the albumin to be transferred onto anexterior of the filler and contact the film 34. As explained above,albumin operates as an insulator. If the albumin migrated onto the filmit would likely jeopardize the integrity of the top seal area. Thus, theconfiguration of the present invention provides a means for eliminatingthis drawback. In testing conducted on the seal integrity of thecontainers 12 of the present invention, 99.90% of the formed containers12 were above the minimum seal strength value of 20 psi in burst testevaluation.

[0061] As explained above, the sheath 86 resides concentrically about aperimeter of the fill tube 84, and an air passageway 88 extends in thespace between the inner diameter of the sheath tube 86 and the outerdiameter of the fill tube 84. While in the preferred embodiment thedistal end portion 100 of the sheath 86 is an adapter that is mounted onthe sheath 86, the distal end portion 100 may be manufactured as part ofthe sheath 86 without destroying the intended function of the sheath 86.As shown in FIGS. 7 and 8, the distal end portion 100 of the sheath 86has a chamfered end 104. A plurality of vent holes 102 are locatedadjacent the end of the distal end portion 100 of the sheath 86. Thesterilized air is dispelled from the air passageway 88 out of the ventholes 102. Since the exit of the vent holes 102 resides at the chamferedend 104 of the sheath 86, the flow pattern of the sterilized air iscircumferentially exterior to the flow pattern of the albumin beingdispelled from the fill tip so as not to interfere with the flow of thealbumin. This decreases the chances of the sterilized air fromintroducing a turbulent effect to the dispensed albumin. Additionally,since the air flow pattern is exterior to and away from the liquid flowpattern of the albumin, any possible foaming of the albumin that maycome in contact with the air is minimized.

[0062] Similar to the benefits uncovered with the dual inner diametersof the fill tube 84, the benefits uncovered with the flow of thesterilized air are extremely useful. Such a configuration greatlyassists in preventing splashing and foaming of the albumin from the exitof the filler. This, prevents contact by the albumin with the portion ofthe film that is converted into the top seal area, thereby also aidingin continually creating a stronger top seal.

[0063] The first interior diameter 106 of the distal end portion 100 ofthe sheath 86 is dimensioned to fit onto the sheath 86 and be securedthereto with a setscrew 110. The second interior diameter 108 of thedistal end portion 100 of the sheath 86 is dimensioned to provide theair passageway 88 between the sheath 86 and the fill tube 84. As shownin FIG. 7, a chamfer 112 is located at the end of the second interiordiameter 108 to further reduce the inside diameter of the sheath 86. Areverse chamfer 114 is located at an exterior portion of the end of thesheath 86.

[0064] The sheath 86 and fill tube 84 are shown as assembled in FIG. 10.As seen in the illustration, the outside diameter of the fill tube 84 isdimensioned to be the same as or slightly less than the reduced insidediameter of the sheath 86 at the chamfer 112. In the preferredembodiment, the second interior diameter of the sheath 86 isapproximately 0.584 inch, and is decreased at the chamfer 112 toapproximately 0.500 inch. Additionally, the outside diameter of the filltube 84 of the preferred embodiment of the present invention isapproximately 0.500 inch. As such, interface between the chamfer 112 andthe fill tube 86 operates to close the air passageway 88 and force thesterilized air out the vent holes 102 located upstream of the exit 92 ofthe second interior passageway of albumin fill tube 84.

[0065] As seen in FIG. 10, the outside diameter of the sheath 86 islarger than the outside diameter of the fill tube 84 protruding past thesheath 86. Often during filling the tube 38 of film contacts the fillingassembly 30. With the identified configuration of the fill tube andsheath, even though during a portion of the filling process the filltube 84 of the filling assembly 30 extends through the opening 80 of thebag and into the cavity 82 of the bag, the sheath 86 is exterior to aportion of the fill tube 84, and thus only the sheath 86 can contact thetube 38, thereby preventing contact between the polymeric container andthe fill tube 84. As such, the exit 92 of the fill tube 84 is positioneda distance away from the interior wall of the flexible polymericcontainer 12. Thus, the position and size of the sheath 86 incombination with the interior interface 98 of the first and secondinterior passageways, and the reverse chamfer 114 prevents any albuminfrom migrating to an exterior of the filling assembly 30 and coming incontact with the seal areas of the tube 38 that ultimately become thetop seal 78 of the finished container. Since albumin operates as aninsulator, it is necessary to maintain all seal areas free of theprotein in order for the polymeric materials to be heat sealed together.If any albumin was present in the seal area prior to sealing, theintegrity of the seal may be jeopardized. As such, with the identifiedconfiguration, the albumin is discharged from the fill tube 84 and intothe bottom of the bag 12 without contacting the seal area of the openingof the bag 12 that ultimately becomes the top seal 78.

[0066] While the specific embodiments have been illustrated anddescribed, numerous modifications come to mind without significantlydeparting from the spirit of the invention, and the scope of protectionis only limited by the scope of the accompanying claims.

We claim:
 1. A method of packaging albumin protein, comprising the stepsof: providing a flexible polymeric container having an opening extendingfrom a cavity of the polymeric container; providing a quantity of aconcentration of albumin in a sterile solution; inserting the albuminunder a solution line pressure from about 4 psig. to about 20 psig. intothe cavity of the polymeric container through the opening therein; and,sealing the opening to secure the liquid albumin within a fluid-tightchamber of the cavity of the polymeric container.
 2. The method of claim1, wherein the albumin is maintained at a temperature of about 68° F.prior to insertion into the cavity of the container.
 3. The method ofclaim 1, wherein the albumin is inserted into the cavity of the flexiblepolymeric container under a solution line pressure from about 12 psig.to about 16 psig.
 4. The method of claim 1, wherein the flexiblepolymeric container is provided within an aseptic environment of aform-fill-seal packaging machine, wherein the albumin is inserted intothe cavity of the flexible polymeric container within the asepticenvironment of the form-fill-seal packaging machine, and wherein theopening of the container is sealed within the aseptic environment of theform-fill-seal packaging machine.
 5. The method of claim 1, furthercomprising the step of providing a filler having a distal tip with firstand second adjacent interior passageways, the first interior passagewayhaving a larger cross-sectional area than the second interiorpassageway, wherein the second interior passageway extending adjacentthe first interior passageway to an exterior of the tip, and wherein thealbumin is dispersed from the filler through the second interiorpassageway.
 6. The method of claim 1, further comprising the step ofproviding a filler having a tip with concentric first and secondinterior passageways, the first interior passageway having an insidediameter being dimensioned larger than an inside diameter of the secondinterior passageway, wherein an interface between the first and secondinterior passageways is interior of an exterior of the tip, wherein thesecond interior passageway extends to the exterior of the tip, andwherein the albumin exits the filler through the second interiorpassageway.
 7. The method of claim 1, further comprising the step ofproviding a sheath exterior a portion adjacent the tip of the filler,the sheath preventing contact between the polymeric container and thefiller.
 8. The method of claim 1, wherein the albumin is provided in a20% concentration.
 9. The method of claim 1, wherein the albumin isprovided in a 25% concentration.
 10. The method of claim 1, wherein theflexible plastic container is provided having a volume of 50 ml.
 11. Themethod of claim 1, wherein the flexible plastic container is providedhaving a volume of 100 ml.
 12. The method of claim 1, further comprisingproviding a flexible polymeric container comprising a laminate filmhaving an outside layer of linear low density polyethylene, a gasbarrier layer, a core layer of polyamide, and an inside layer of linearlow density polyethylene, the layers being bonded together by apolyurethane adhesive.
 13. A method of packaging albumin protein in aseries of flexible polymeric containers, comprising the steps of:providing a quantity of filtered albumin; providing a flexible polymericmaterial; providing a form-fill-seal packaging machine and convertingthe flexible polymeric material into a series of bags in theform-fill-seal packaging machine; filling the bags with a quantity ofalbumin within the form-fill-seal packaging machine; and, sealing a sealarea of the bags with the packaging machine to enclose the quantity ofthe albumin within the bags.
 14. The method of claim 13, whereinadjacent bags in the series of bags are initially connected, and areseparated following the filling of each bag.
 15. The method of claim 14,further comprising providing a forming mandrel in the form-fill-sealpackaging machine.
 16. The method of claim 15, further comprisingforming the flexible polymeric material into a tube with the formingmandrel, and further forming the tube into the series of adjacent bags.17. The method of claim 13, wherein the bags are sequentially filledwith the quantity of albumin.
 18. The method of claim 13, furthercomprising heat sealing a periphery of the bags to enclose the quantityof the albumin within the bags.
 19. The method of claim 13, furthercomprising providing a flexible polymeric container comprising alaminate film having an outside layer of linear low densitypolyethylene, a gas barrier layer, a core layer of polyamide, and aninside layer of linear low density polyethylene, the layers being bondedtogether by a polyurethane adhesive.
 20. The method of claim 13, whereinthe form-fill-seal packaging machine has an aseptic area, wherein asterilized flexible polymeric material is provided within the asepticarea, wherein the sterilized flexible polymeric material is formed intoa series of adjacent bags within the aseptic area, wherein the albuminis sequentially inserted into the bags in the aseptic area, and whereinthe bags are sequentially sealed within the aseptic area to form afluid-tight container.
 21. The method of claim 13, further comprisingthe step of providing a repeating filler having a tip with concentricfirst and second interior passageways, the first interior passagewayhaving a cross-sectional area greater than a cross-sectional area of thesecond interior passageway, wherein an interface between the first andsecond interior passageways is interior of an exterior of the tip,wherein the second interior passageway extends to the exterior of thetip, wherein the albumin exits the filler through the second interiorpassageway, and wherein the albumin is maintained at the interfacebetween the first and second interior passageways during a suspension offilling.
 22. The method of claim 21, further comprising the step ofproviding a sheath exterior to a portion adjacent the tip of the filler,the sheath limiting contact between the polymeric container and thefiller.
 23. The method of claim 21, further comprising the step ofproviding an exterior sheath concentric with the filler, and an airpassageway extending between an interior of the sheath and an exteriorof the filler, wherein the sheath limits contact between the polymericcontainer and the filler, and wherein sterilized air passes through theair passageway and is expelled adjacent the tip of the filler andupstream of the albumin exit.
 24. The method of claim 13, furthercomprising the step of filtering the albumin through a 0.2 micronfilter.
 25. A method of packaging albumin protein in a series offlexible polymeric containers, comprising the steps of: providing aquantity of filtered albumin; providing a flexible polymeric material;providing a form-fill-seal packaging machine and converting the flexiblepolymeric material into a tube with a former in the form-fill-sealpackaging machine; converting the tube into a series of bags in theform-fill-seal packaging machine; filling the bags, through an openingin the bags, with a quantity of albumin within the form-fill-sealpackaging machine; and, sealing a seal area of the opening of the bagswith the packaging machine to enclose the quantity of the albumin withinthe bags.
 26. The method of claim 25, wherein the bags are sequentiallyfilled with the quantity of albumin.
 27. The method of claim 25, furthercomprising a filler discharging albumin from the filler and into the bagwithout contacting the seal area of the opening of the bag.
 28. Aprocess of packaging albumin in a flexible polymeric container,comprising the steps of: providing a concentrate of albumin; providing apackaging machine having a filling assembly and a sealing assembly, thefilling and sealing assemblies being located within an interior asepticenvironment of the packaging machine; providing a sterile flexiblepolymeric container having an opening extending into a cavity; fillingthe container with albumin under pressure through the filling assemblywithin the aseptic area of the packaging machine, the filling assemblyhaving a fill tube exit positioned a distance from a wall of theflexible polymeric container, the fill tube exit directing the albumininto the cavity of the container distal the periphery of the opening ofthe container, and the fill tube maintaining the albumin in the filltube a distance from the fill tube exit during filling suspension; and,sealing the opening of the container within the aseptic area of thepackaging machine to retain the albumin within the cavity of thecontainer.
 29. The method of claim 28, further comprising the step ofproviding a sheath exterior to a portion of the filling assembly, thesheath limiting contact between the polymeric container and the fillingassembly.
 30. A process of packaging albumin in a flexible polymericcontainer, comprising the steps of: providing a concentrate of albumin;providing a packaging machine having a forming assembly, a fillingassembly, and a sealing assembly, each of which is located within aninterior aseptic environment of the packaging machine; providing aflexible polymeric film; forming the flexible polymeric film into anelongated tube with the forming assembly; sealing a portion of theelongated tube of polymeric film with the sealing assembly, the sealedpolymeric film being dimensioned in the shape of a bag having seal areasabout a periphery thereof, a cavity located within the bag and betweenthe seal areas, and an opening extending from the cavity to an exteriorof the bag; filling the bag with albumin under a solution line pressurethrough the filling assembly, the filling assembly having a fill tubeextending through the opening of the bag and into the cavity of the bag,and a sheath concentric to an exterior of the fill tube, the fill tubedirecting the albumin into an interior of the bag a distance away from aperiphery of the opening of the bag, and the sheath limiting contactbetween the fill tube and the bag; and, sealing the opening of the bagto retain the albumin within the cavity of the bag.
 31. The process ofclaim 30, wherein the seal areas are provided about the entire peripheryof the bag except for the opening.
 32. The process of claim 30, furthercomprising converting the tube into a plurality of adjacent bags. 33.The process of claim 32, further comprising sealing at least three sidesof the bags.
 34. The process of claim 32, further comprisingsequentially filling the bags with the quantity of albumin.
 35. Theprocess of claim 34, further comprising sequentially sealing the openingof the bags.
 36. The process of claim 30, wherein the filling stepcomprises providing a filler having a tip with concentric first andsecond interior passageways, the first interior passageway having across-sectional area greater than a cross-sectional area of the secondinterior passageway, wherein an interface between the first and secondinterior passageways is interior of an exterior of the tip, wherein thesecond interior passageway extends to the exterior of the tip, whereinthe albumin exits the filler through the second interior passageway, andwherein the albumin is maintained at the interface between the first andsecond interior passageways during a suspension of filling.
 37. Aflexible polymeric container for holding a concentrate of water-solublealbumin, comprising: a bag made from a sheet of flexible polymericmaterial initially converted into a tube with a former, the tube beingsubsequently converted into a series of adjacent bags in an aseptic areaof a form-fill-seal packaging machine, the bags having a first sidemember, a second side member peripherally sealed to the first sidemember, and a cavity between an interior of the first and second sidemembers, wherein a quantity of a concentration of water-soluble albuminis located within the cavity of the bag following sequential filling ofthe albumin into the cavity of adjacent bags through an opening of thebags with a filler in the aseptic area of the form-fill-seal packagingmachine, the opening of the bags being sealed sequentially within theaseptic area of the form-fill-seal packaging machine to create afluid-tight chamber.
 38. The flexible polymeric container of claim 37,wherein the flexible polymeric sheet material comprises a laminate filmhaving an outside layer of linear low density polyethylene, a gasbarrier layer, a core layer of polyamide, and an inside layer of linearlow density polyethylene, the layers being bonded together by apolyurethane adhesive.
 39. The flexible polymeric container of claim 38,wherein the gas barrier layer is a polyvinylidene chloride.
 40. Theflexible polymeric container of claim 37, wherein the core layer ofpolyamide is a nylon.
 41. The flexible polymeric container of claim 38,wherein the gas barrier layer is constructed from SARAN.
 42. A flexiblepolymeric container filled with albumin, comprising: an outer shell madeof a flexible polymeric sheet material, the material comprising alaminate film having an outside layer of linear low density polyethyleneadhesively bonded together with a polyurethane adhesive to a first sideof a polyvinylidene chloride layer, a second side of the polyvinylidenechloride layer being adhesively bonded together to a first side of alayer of SARAN, the second side of the layer of SARAN being adhesivelybonded together with a polyurethane adhesive to an inside layer oflinear low density polyethylene, the outer shell having a first side andan opposing second side heat sealed together at a periphery of the outershell, and a cavity located between the first and second sides, thecavity forming a fluid-tight chamber having a concentration of albuminstored therein, wherein a fitment extends from the outer shell, thefitment having a sealed passageway extending into the cavity of thecontainer to allow the albumin to be released from the fluid-tightchamber.
 43. A container for holding albumin comprising: a sheet offlexible polymeric film formed into a bag having a cavity enclosed by afirst wall, an opposing second wall, and seals about a periphery of thefirst and second walls, the seals joining an interior portion of theopposing first and second walls and creating a fluid-tight chamberwithin the cavity of the container, wherein a concentration of albuminmixed with a solution of sterile water and stabilizers is stored withinthe fluid-tight chamber.
 44. The container of claim 43, wherein the baghas a plurality of peripheral edges, three of the peripheral edges beingsealed with heat, and one of the peripheral edges containing a fold thatseparates the first wall from the opposing second wall.
 45. Thecontainer of claim 44, wherein a fitment is connected to the containeradjacent the fold, the fitment having a passageway that cooperates withthe fluid-tight chamber of the container.
 46. The container of claim 44,wherein the peripheral edge opposing the fold contains a firstlongitudinal seal and a second longitudinal seal, the first and secondlongitudinal seals joining the first and second opposing walls, andwherein an aperture is located between the first longitudinal seal andthe second longitudinal seal, the aperture extending through the firstand second opposing walls.
 47. The container of claim 45, furthercomprising at least one chevron seal in the fold.
 48. The container ofclaim 45, farther comprising a chevron seal in the fold on opposingsides of the fitment.